Outcomes and Prognostic Factors of Metastatic Gastric Cancer: A Single-Center Experience

Background Gastric cancer (GC) carries a poor survival outcome despite the availability of many therapeutic agents active in treatment. In this study, we aimed to evaluate the survival outcomes of metastatic GC treatment from a single center in Saudi Arabia and identify possible prognostic factors. Methodology Data on patients diagnosed with metastatic GC between December 2009 and November 2013 were collected and analyzed. Results During this period, 41 patients were diagnosed with a median age at diagnosis of 52 years, and 56.1% of patients were males. Only four (9.2%) patients had human epidermal growth factor receptor 2 overexpression. Overall, 83% were treated with oxaliplatin-based chemotherapy. The median progression-free survival (PFS) and overall survival (OS) were 4.1 and 15.4 months, respectively. Female sex was an independent prognostic factor for better PFS and OS. Normal lymphocyte count was associated with improved PFS. Conclusions Our study highlights poor outcomes in patients with metastatic GC and the need for further research in this field.


Introduction
Gastric cancer (GC) is the fifth most common cancer and the fourth most common cause of cancer-related death worldwide [1]. Due to a lack of early symptoms, GC often presents in an advanced stage, characterized by poor survival [2]. The survival rates for advanced GC are among the worst of most solid tumors, with a median survival time of four months without systemic chemotherapy [3].
Systemic therapy has been shown to extend survival compared to the best supportive care in the advanced stage [4][5][6][7]. Despite the availability of many new chemotherapeutic, biological, and immune targeting agents, the outcome continues to be poor for patients with metastatic disease, with median overall survival (OS) of 8-16 months.
The management of patients with metastatic GC continues to be a challenging process. There is no standard first-line chemotherapy regimen, and several options are available and considered acceptable. First-line therapy usually consists of fluoropyrimidine and a platinum compound. However, some regimens incorporate irinotecan and taxanes in the first-line treatment. Around 20% of patients with GC have human epidermal growth factor receptor 2 (HER-2) overexpression. Adding trastuzumab to first-line, platinumbased chemotherapy in this group of patients has improved survival [4,5]. Recently, checkpoint inhibitors have been incorporated in the first-line setting with improvement in survival [5,7].
Few real-world data address the treatment pattern and outcomes of patients with metastatic GC from Saudi Arabia. In this report, we evaluate the treatment outcomes of patients with metastatic GC treated with systemic therapy at a tertiary care institution in Saudi Arabia. We also discuss the relevant prognostic factors in this group of patients.

Materials And Methods
The

Results
A total of 41 patients with metastatic gastric/GEJ adenocarcinoma who received palliative chemotherapy were eligible for analysis. The median age at diagnosis was 52 years (range = 15-75 years). In total, 23 (56.1%) patients were males, with a male-to-female ratio of 1.27:1. Moreover, 19 (46%) patients had ECOG PS of 0-1. More than half of our patients (53.6%) were adenocarcinoma Not Otherwise Specified (NOS), followed by signet ring differentiation (29.3%) and intestinal subtype in (12.2%). In total, 24 (58.5%) patients had poorly differentiated histological grades, followed by 36.6% with moderately differentiated grades. The most common primary site at diagnosis was distal GC, accounting for 41.5%, followed by GEJ (19.5%). Of note, 58.5% of patients had synchronous metastasis in two or more organs. The most common site of metastasis were lymph nodes (48.8%), followed by the peritoneum (43.9%) and liver (39%). Out of 28 patients tested for HER-2 expression by immunohistochemistry (IHC), four (9.8%) patients had HER-2 overexpression. Patient characteristics are illustrated in Table 1.

FIGURE 1: Kaplan-Meier plots of (A) progression-free survival and (B)
overall survival (OS) in patients treated for metastatic gastric cancer.

Discussion
This study characterizes the outcomes and prognostic factors of metastatic GC/GEJ adenocarcinoma treated at a tertiary center in Saudi Arabia. The median age at diagnosis in our patients was 52 years, which is younger than most reported literature from the Middle East, the far East, and the Western Hemisphere, where the median age in the latter is around 65 years [3,[8][9][10][11][12][13]. This might be explained partially by the younger population of Saudi Arabia; however, other possible factors need to be sought. The male-to-female predominance was also less evident in our patient population than in reports from different parts of the world, where the ratio is approximately 1.8:1 [3,[8][9][10][11].
The rate of GEJ as a primary disease site was 19.5%, comparable to the Eastern Hemisphere [8,14]; however, slightly less than the reported GEJ rate in the Western Hemisphere [9,15,16]. GEJ cancer is related to the higher incidence of gastroesophageal reflux disease (GERD) and obesity [17]. It is expected that GEJ cancer will increase in the Saudi population as the rate of obesity is increasing, as has been reported [18]. In our study, not all patients were tested for HER-2 status. Out of 28 patients tested, only four were HER-2 overexpressed by IHC, representing 9.8%. This represents one of the lowest reported HER-2 positivity in patients with metastatic GC [19]. Patients with treated HER-2-positive GC have improved survival compared to the HER-2-negative group. This might be one of the factors that resulted in a low PFS in our patient cohort.
The ORR in our patient's cohort was lower than that reported in previous trials, with an ORR of 14.6% [20]. This can be explained due to more patients with PS of 2-4 in our study compared to clinical trials.
The median PFS in our study was disappointingly low at 4.1 months compared to reported data in the literature [10,14,20]. This inferior PFS can likely be explained by a higher percentage of patients with ECOG-PS of 2-4, accounting for 39% of our patient cohort [8,10,16]. The low rate of second-line treatment in our patient cohort of 36% also suggests a group of patients with poor characteristics, making them unfit for second-line therapy. In recent trials, second-line therapy has generally been delivered to 40-55% of patients receiving first-line treatment [21,22].
The median OS was 15.4 months, with a five-year survival of 39% vs. 12% in previous population-based survival in Saudi Arabia [23]. Whether the younger age of our patient cohort (median = 52 years) or the small sample size played a role in the higher survival rate is not entirely clear [3,9,10,24]. We were unable to obtain the dose intensity of chemotherapy in our patients. This is also an issue of debate where some trials have documented similar survival in elderly frail patients with poor PS with up to 40% dose reduction with oxaliplatin-based chemotherapy [25].
Multiple reports in the literature have studied the potential prognostic factors for metastatic gastric/GEJ cancer. In our study, the female sex was associated with significantly better PFS and OS by univariate and multivariate analysis, similar to other reports [3,9]. Additionally, normal lymphocyte count was associated with significant improvement in PFS in both univariate and multivariate analysis. This is comparable to reports confirming low neutrophil-to-lymphocyte ratio (NLR) associated with better PFS [26,27]. Patients with low NLR are expected to have a normal-high lymphocyte count.
The retrospective nature of our research, the small number of our cohort, and the lack of chemotherapy dose intensity are the main limitations of our study; however, it is the most extensive series from Saudi Arabia. Every effort should be made to improve on the current results. This would be achieved by early diagnosis and accessibility of patients to therapy and using a modern regimen containing immune checkpoint inhibitors.

Conclusions
Metastatic GC in our part of the world continues to have poor outcomes. Despite the incorporation of immune checkpoint inhibitors lately as a new standard of care in the first-line setting, the outcome continues to be poor and warrants further research. Female sex and normal baseline lymphocyte count were independent prognostic factors associated with a better PFS, while female sex was an independent factor for better OS in metastatic GC patients.

Additional Information Disclosures
Human subjects: Consent was obtained or waived by all participants in this study. Research Ethics Committee issued approval RAC 2161-128. The study was approved by the hospital Research Ethics Committee, under the number RAC 2161-128. Given the study's retrospective nature, the hospital Research Ethics Committee approved a waiver of consent. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.